December 9, 2020

Nobel Laureate Michael Houghton leads Applied Virology Institute at University of Alberta

Alberta Innovates investments help Houghton and colleagues in their search for vaccines and treatments for hep C, COVID-19 and other major diseases

 

Illustration by Scott Carmichael

The Challenge: To translate medical research into vaccines and treatments.

Alberta Investment: $32.5 million from Government of Alberta, administered by Alberta Innovates, to match original Li Ka Shing Foundation donation and to support applied virology projects with commercial potential. Additional funding from Alberta Innovates includes a $5 million Collaborative Research & Innovation Opportunity (CRIO) award towards HCV vaccine development; $500,000 towards trainees, post-doctoral fellows and COVID-19 vaccine development.

Funding leveraged from other sources: $3 million from Western Economic Development. $1.7 million from Canadian Institutes of Health Research (CIHR) for COVID-19 therapeutics; $750,000 from CIHR for COVID-19 vaccines.

The Impact: Under the leadership of Dr. Michael Houghton and Dr. Lorne Tyrrell, more than 24 professors and their researchers have been able to advance their work through the AVI. Highlights:

  • World-leading HCV vaccine candidate designed, now being manufactured for clinical trials around the world.
  • Co-sponsoring clinical testing of a Group A Streptococcus vaccine in Alberta.
  • Planning Phase 1 clinical trial of a novel COVID-19 protease inhibitor.
  • Testing a novel COVID-19 vaccine in the lab.
  • Novel antivirals identified for cytomegalovirus (CMV).
  • Novel drugs designed computationally and chemically shown to be active in Alzheimer’s mouse model.
  • Computationally-derived drugs shown to be active in cellular models of non-alcoholic fatty liver disease.
  • Early-stage computationally-designed drugs targeting immune checkpoints for cancer therapy

Viruses are a complicated bunch. Much smaller than bacteria, viruses require a host cell to survive. Once inside a host, they multiply by taking over, forcing the cell to reproduce the pathogen. If left untreated, some viruses like hepatitis C and the novel coronavirus that causes COVID-19 can have dreadful effects. Only vaccinations or antiviral medications effectively neutralize a virus.

Meet Michael Houghton

Dr. Houghton was born and educated in England. A few years after graduating with his PhD in biochemistry he moved to sunny California where he co-discovered the hepatitis C virus before coming to Alberta.

Houghton has over 70 patents to his credit, and is listed as a co-inventor on around 10 while at the University of Alberta.

In 2000, he was awarded the Lasker Prize for his role in the discovery of the hepatitis c virus. In 2013, he was awarded the Canada Gairdner International Award,  but declined it,  because the award committee would not recognize his lab partners. “I very much feel that they deserve to share it with me. I didn’t have all the good ideas, and I didn’t do all the work.”

The lab is where the main war is waged. To be more effective, researchers need a way to quickly translate their research into clinical application. Enter the University of Alberta’s Li Ka Shing Applied Virology Institute (AVI), a unique institution that has the expertise and the tools to do just that.

It’s a world-class institute with a full complement of biotechnologies required to produce diagnostics, vaccines and therapeutic drugs. The AVI is able to develop drug treatments by analyzing massive amounts of complex data through computer calculations, a process called computational drug discovery.

“There are very few universities in the whole world that have an applied institute like this one that is trying to take research innovations into the clinic. That’s very unusual for a university anywhere,” says Dr. Michael Houghton, director of the AVI.

And now the AVI also has a Nobel laureate on staff. Houghton made Alberta and Canada proud in October when he shared a Nobel prize for his past work in discovering the hepatitis C virus (HCV).

Today, at the AVI, Houghton’s team is closing in on a vaccine to beat hep C and he is also working on a vaccine for COVID-19. “The AVI is here to get across what’s called the valley of death, which is the gap between research innovation and clinical proof of principle followed by commercialization,” Houghton says. “The ideal is to do great research, show that it works in the clinic, and then commercialize it here in Alberta and with global partners.

“I have seen this model work so well at the Chiron Corporation in California where we discovered HCV and developed blood tests now used all around the world.  Big discoveries like this are very good for patients as well as generating income for the host institution and province. But it takes many years to succeed,” he notes.

Translating research into use

The AVI is housed within the Li Ka Shing Institute of Virology at the University of Alberta founded in 2010 by its director, Dr. Lorne Tyrrell.

The AVI opened its doors within Li Ka Shing in 2013 to translate research into use. It is home to experts in fields that span virology, immunology, medicinal and synthetic chemistry, mammalian cell bioreactors, and is a leader in using artificial intelligence for computational drug design.

AVI harnesses the power of big data

The Applied Virology Institute decided to build on the excellent computational drug discovery work pioneered at the University of Alberta.

“Using an IBM supercomputer and Compute Canada, brilliant [U of A] computational scientists like Dr. Kamlesh Sahu and Prof. Khaled Barakat have come up with hit drugs targeting protein interactions of crucial importance in many diseases such as cancer and neurological and metabolic diseases,” Houghton says. “Such computational science is quickly generating active compounds that are then derivatized and improved by our chemistry team.

“This represents a new, exciting era in drug discovery. In addition, we are using such technology to produce tools that better predict drug cardiotoxicity along with Dr. Sergei Noskov’s artificial intelligence laboratory at U of Calgary.”

The AVI’s access to the IBM supercomputer to identify the right small molecules is where Sahu, Barakat and the institute really shine. Dr. Holly Freedman of the AVI also used state-of-art hardware and software to predict the structure of the hep C virus, a model now being tested by the U.S. National Institutes of Health in collaboration with Houghton’s team.

In addition, the AVI collaborates with the Alberta Cell Therapy Manufacturing (ACTM) facility next door, which is being used to manufacture the hep C vaccine developed by Houghton’s team in preparation for clinical testing in people in 2021.

The Alberta government and Alberta Innovates have funded the AVI and its use of “big data” and artificial intelligence from the outset, along with co-funders Western Economic Diversification, the Canadian Institutes of Health Research and the Li Ka Shing Foundation.

Hepatitis C – controlling disease, reducing health care costs

Houghton discovered the hepatitis C virus in 1989 with his collaborators Qui-Lim Choo and George Kuo while working at a small American startup called Chiron. Houghton and his colleagues then turned their attention to developing a vaccine to eradicate the newly identified virus. Work, however, was difficult.

Years later, an enticement in the form of a Canada Excellence Research Chair in Virology, and the prospects of working more closely with Tyrrell, lured Houghton north to the University of Alberta and its newly established Li Ka Shing Institute of Virology.  “I recall a meeting I had with Mr. Li at that time and he stressed his desire ‘to see the research bring benefit to patients.’ This concurred with my desires, and I am proud to be the ‘Li Ka Shing Professor of Virology in the Institute,’ ” Houghton says.

Li Ka Shing, a global entrepreneur based in Hong Kong, is one of the world’s major philanthropists.

Houghton’s work continued and a breakthrough came in 2013. His team at AVI published seminal findings from one of his senior research assistants, Dr. John Law, showing their vaccine could neutralize the infectivity of most global hep C strains in cell cultures. Subsequent work by students Jason Wong and Janelle Johnson showed the mechanism at work, and the vaccine is now being manufactured using a process devised by another senior research assistant, Dr. Michael Logan.

Hepatitis is the first chronic viral infection in humans that is curable, but the new, potent antivirals are very expensive. “A preventative vaccine would not only stop up to 12,000 Canadians from becoming infected every year, but would be highly cost-effective and save many hundreds of millions of dollars from Alberta’s health-care budget,” Houghton says. He notes that the cost of treating all Canada’s hep C patients with the antivirals would be in the billions of dollars, whereas a vaccine can prevent disease in the highest-risk groups at a cost of just $20-50 million.

Essential – a vaccine against COVID-19

Other vaccines and treatments under development at AVI

  • Michael Good (Griffiths University in Australia and an adjunct professor at the U of A) has developed a vaccine against Group A Streptococcus, a major cause of rheumatic heart disease around the world. The AVI is sponsoring a clinical trial in the Northern Alberta Clinical Trials & Research Centre in Edmonton. Currently, the AVI is waiting for Health Canada to review its clinical trial application.
  • Jim Nieman and his chemistry group in the AVI are getting close to developing a novel antiviral against human cytomegalovirus (CMV), a common herpes virus that can cause complications in pregnancy and in people with weakened immune systems.
  • In 2013, Sciencemagazine proclaimed cancer immunotherapy as the scientific breakthrough of the year. Cancer immunotherapy involves blocking something called immune checkpoints that exist on T cells, our immune system’s primary defence against tumours, using antibodies.

“Cancer is very smart. It can deactivate the T cells,” says Houghton. “This leaves our body open to the growth of malignant tumours.” The AVI has worked with Dr. Barakat from the Faculty of Pharmacy and Pharmaceutical Sciences to develop drugs that can be taken orally rather than using antibodies to do the work. “We want to develop drugs that are rapidly turned over in the body, so that if a patient gets a strong side effect, we can just simply stop drug therapy,” Houghton says.

The COVID-19 pandemic continues to grow, and a vaccine is essential. Houghton and his team are also developing a COVID-19 vaccine with seed funding from the Canadian Institutes of Health Research and Alberta Innovates. Their vaccine is unique in using just a small part of the virion spike protein (the “spikes” seen on the outside of the coronavirus particle covered in a protein shell) to neutralize its infectivity.

Since COVID-19 is a disease of the respiratory tract initially, Houghton and his team are collaborating with overseas groups who are supplying mucosal adjuvants (vaccine additives) to try to boost protective immunity in the respiratory tracts. Should the current COVID vaccines in Phase 3 trials elsewhere not prove effective, Houghton’s strategy can be an alternate one to contain the pandemic.

Moreover, Tyrrell is putting together a clinical trial application to Health Canada to test a cat coronavirus drug in COVID-19 patients. He and colleagues in the U of A laboratories of Dr. Joanne Lemieux and Dr. John Vederas recently published a high-profile paper in the scientific journal Nature Communications showing that a drug used to save the lives of cats infected with a feline coronavirus inhibits the COVID-19 virus in cell cultures. The AVI’s Dr. Jim Nieman and colleagues are working on other very promising inhibitors of SARS-CoV-2, the coronavirus causing COVID-19.

Alberta a centre of cutting-edge virology research

Houghton speaks positively about the role that computational sciences are playing in health research, and the AVI’s work is demonstrating as much.

The biggest drug companies in the world screen their drugs in what’s called a wet lab, and they will screen probably half a million drugs taking several months, he says. “Computationally, we can now screen billions in just several weeks. I think we are ahead of big pharma in this regard, so we have this window of opportunity in Alberta.

“Hopefully we can be at the cutting edge of all that. We want to be able to tell Albertans that we’ve innovated medically though new drugs and vaccines,” he says. “The AVI at the U of A is a unique place. It’s very exciting for me to be working here because we’ve got so many new opportunities to explore. It’s been the most stimulating phase of my career, here at the University to Alberta. It’s also been the hardest work I’ve ever done.”

Coming from a Nobel laureate, it’s high praise for what should be considered a crown jewel of Alberta research centres.